Role of Integrin-linked kinase in extracellular matrix remodeling and cell fate decisions

Abstract

The extracellular matrix (ECM) functions as a structural scaffold for tissues and regulates signaling by interacting with specific receptors and by providing a reservoir for growth factors. This multitude of functions makes the ECM an essential regulator of organ development and maintenance. The deposition and remodeling of the ECM into a precise configuration is a cell-dependent process that requires integrin adhesion receptors and the generation of cellular forces. However, it is not clear how integrins transduce force necessary for ECM remodeling. In addition, the role of ECM remodeling in directing cell fate decisions in vivo is not completely understood. Integrin-linked kinase (ILK) is an essential adaptor protein that binds to β1- and β3- integrin cytoplasmic tails and links them to the actin cytoskeleton. The aim of this study was to analyze the function of ILK in ECM remodeling and the role of this process in the regulation of stem cell (SC) fate. In vitro experiments revealed that ILK is required for cellular force generation, cell-matrix adhesion maturation, and subsequent remodeling of a fibronectin matrix. Using various strategies to delete ILK in murine epidermis, it was further shown that ILK regulates SC fate within hair follicles (HFs). Deletion of ILK led to gradual loss of HFSCs due to their aberrant activation and enhanced differentiation. Furthermore, ILK was observed to regulate the precise composition of the basement membrane (BM) SC niche. The inverse gradients of laminin-(LN) 511 and LN-332 present in the skin of wild type mice was lost upon deletion of ILK. As a consequence, Wnt and Tgf-β signaling pathways that were shown to be modulated by LN-511 and LN-332, were dysregulated causing aberrant SC activation. Consequently, reconstituting a wild type ECM restored the activities of Wnt and Tgf-β pathways in ILK-deficient cells to the level of controls. The aberrant SC activation was observed to cause replication stress and accumulation of DNA damage, which predisposed ILK-deficient mice to skin carcinogenesis. Taken together, this study identifies a critical role for ILK in ECM remodeling and highlights the importance of reciprocal cell-ECM interactions in cell fate decisions and tissue homeostasis.